Patent GB-390831-A (GB)
Title: Process for the manufacture of new therapeutic compounds of the heterocyclic series
Filed: 1931-09-03
Abstract: Heterocyclic quaternary compounds containing acidylamino residues are prepared by combining the amino group of a heterocyclic or aromatic-heterocyclic compound, of which a cyclic nitrogen atom is in the quaternary state, by means of a carbonic, thiocarbonic, sulphuric or sulphurous acid residue in an amide-like manner with an amino or substituted amino group, with a substituted aromatic residue, or with a substituted or unsubstituted heterocyclic or aromatic-heterocyclic residue.  The formation of the quaternary compound may take place before, during or after the synthesis, by any known method, of the base compound.  The products possess therapeutic properties. According to the examples, (1) 6-aminoquinoline is heated with 3 - nitro - 4 - methyl - 1 - benzoyl chloride and the resulting m-nitro-p-toluyl-6-aminoquinoline converted into its quaternary dimethyl sulphate, methyl chloride and ethyl-p-toluenesulphonate compounds; the methyl chloride and dimethyl sulphate compounds of m-nitro-p-toluyl-3 and 7-aminoquinolines are similarly prepared, also the ethyl-p-toluene-sulphonate and benzyl chloride compounds of m - nitro - p - toluyl - 6 - aminoquinoline and the methylquinolinium chloride of m-nitrobenzoyl - 6 - aminoquinoline; m-nitro - p - toluyl-6-amino - b  - ketopropylquinolinium chloride is prepared by acting upon m-nitro-p-toluyl-6 - aminoquinoline with monochloracetone; (2) m-nitro-p-toluyl-6-aminomethylquinolinium methyl sulphate is reduced and acetylated, giving the m-acetylamino compound; the corresponding methylquinolinium chloride is referred to; (3) 6-aminoquinoline is heated with p-nitrotoluene-o-sulphochloride and the resulting p-nitrotoluene-o-sulpho-6-aminoquinoline converted into its methyl chloride and dimethyl sulphate compounds; (4) m-amino-p-toluyl-6-aminomethylquinolinium chloride is condensed with m-chlorobenzoyl chloride to form m-(m-chlorobenzoylamino)-p-toluyl-6-aminomethylquinolinium chloride; (5) m-nitro-p-toluyl-5-aminoisoquinoline, obtained from 5-aminoisoquinoline and m-nitro-p-toluylchloride, is treated with dimethyl sulphate; (6) m-nitro-p-toluylBz-amino-o-phenanthroline, prepared from m - nitro - p - toluylchloride and Bz - amino - o - phenanthroline, is converted with dimethyl sulphate into its bis-quarternary compound; (7) 6-aminoquinoline is treated with phosgene and the resulting urea transformed into its methyl chloride, methyl iodide and dimethyl sulphate bis-compounds; similar products are prepared from 5 and 7-aminoquinolines and 6-methylaminoquinoline; nitration of the quaternary compounds of N : N<1>-diquinolyl-6-urea and precipitation with hydrochloric acid or sodium chloride yields the bis-chloromethylate of N : N<1>-di-5-nitroquinolyl-6-urea; by treatment of N : N<1>-diquinolyl-6-urea with one molecular proportion of dimethyl sulphate, N-(quinolyl-6-)-N<1>-(methylquinoliniummethyl - sulphate-6-) urea is produced; (8) the bismethylsulphate of bis-(N : N<1>-6-methoxy-5-quinolyl)-urea is obtained from 5-amino-6-methoxyquinoline by the process of the preceding example; (9) the methylsulphate of the symmetrical urea of 3-aminocarbolidine (see Specification 360,027) is obtained by the process of (7) from 3-aminocarbolidine; (10) di-(8-methyl-6-quinolyl)-thiourea is prepared by treating 6-amino-8-methylquinoline with thiophosgene or by boiling it with carbon bisulphide; the methylsulphate and bis-chloromethylates are described; similar quaternary compounds are prepared of the thioureas from 5-, 6- and 7-aminoquinolines and from 3-aminoquinaldine; (11) m-nitro-p-toluyl-6-aminoquinoline is reduced, treated with phosgene, and the resulting urea converted into its dimethyl sulphate and methyl chloride compounds; the latter compound is also obtained by treating m-amino-p-toluyl-6-aminomethylquinoliniumchloride with phosgene or by condensing 6-aminomethylquinolinium chloride (2 mols.) with 1 : 1<1>-dimethyl-2 : 2<1>-diphenylurea-4 : 4<1>-dicarboxylic acid chloride (1 mol.); (12) 6-quinolylthiourea is formed from 6-aminoquinoline and potassium thiocyanate and converted with dimethyl sulphate; the corresponding methylquinolinium chloride is obtained by precipitating the methylsulphate solution with hydrochloric acid or sodium chloride or by the action of potassium thiocyanate on 6-aminomethylquinolinium chloride; (13) by heating g -aminopyridine (2 mols.) with phenol carbonate (1 mol.), di-g -pyridylurea is obtained; treatment of the dimethyl sulphate compound with nitric acid and precipitation with sodium chloride yields a mononitro derivative of the bis-methylchloride of di-g -pyridylurea; (14) 6-aminoquinoline heated with 2-methyl-4-quinoline carboxylic acid ethylester or acid chloride gives an amide which is converted into quaternary compounds with dimethyl sulphate and methyl chloride; (15) the product obtained by condensing 2-aminoquinoline with m-nitro-p-toluyl chloride is transformed into its quaternary compound with dimethyl sulphate; the same compound results when 2-chloroquinolinium methyl sulphate is treated with m-nitro-p-toluylamide; (16) N-(quinolyl-6)-N<1>-(6-methoxyquinolyl-8)-urea is prepared by interaction of quinoline-6-carbon-azide (1 mol.) with 6-methoxy-8-aminoquinoline (1 mol.); by treatment with one molecular proportion of dimethyl sulphate, N-(methylquinoliniummethylsulphate-6) -N<1>-(6-methoxyquinolyl-8)-urea is obtained; ureas are prepared in a similar manner by interaction of quinoline-6-carbonazide with the following amino compounds, viz. 1-phenyl-2 : 3-dimethyl-4-amino-5-pyrazolone, N-methyl-1 : 2 : 3 : 4-tetrahydro-6-aminoquinoline, 6-(m-amino-p-toluylamino)-quinoline, 3-diethylamino-ethoxyaniline, 6 - (p - aminophenoxy) - quinoline, 4 - amino-3<1> : 5<1>-dimethyldiphenylether, 5-amino-isoquinoline, 7-aminoquinoline and 5-chloro-8-aminoisoquinoline, and converted into their quaternary methylsulphate compounds; by the action of 2 mols. of quinoline-6-carbonazide with 1 mol. of 1 : 2 : 3 : 4-tetrahydro-6-aminoquinoline, there is obtained N-(quinolyl-6)-N<1>-[1-(N-quinolyl-6-carbamino) - 1 : 2 : 3 : 4-tetra-hydroquinolyl-6]-urea which gives a bis-methyl-sulphate compound; (17) 6-aminoquinoline is treated with m-nitro-p-toluic p acid azide and the resulting N-(quinolyl-6)-N<1>-(m-nitro-p-tolyl)-urea converted into its methylsulphate compound, which is then reduced to the corresponding m-amino body; in a similar manner, N-(quinolyl-6)-N<1>-(4-dimethylaminophenyl-1)-urea is obtained from 6-aminoquinoline and p-dimethylaminobenzoyl azide and converted into its bis-chloromethylate; (18) quinoline-6-carbohydrazide is converted by means of dimethyl sulphate followed by hydrochloric acid into methylquinoliniumchloride-6-carbo-hydrazide, which is then treated with sodium nitrite; after addition of sodium iodide the bis-iodomethylate of N : N<1>-diquinolyl-6-urea separates out; (19) 6-biguanyl-methylquinoliniumchloride, obtained by reacting dicyandiamide with 6 - aminomethylquinolinium-chloride, is added to sulphuric acid, cooled with ice and treated with hydrochloric acid when 6-guanylcarbaminomethylquinolinium chloride sulphate precipitates; (20) quinoline-6-carbon-azide is reacted with quinoline-6-carbohydrazide and the resulting 6-quinolinecarbonyl-6<1>-quinolylsemicarbazide converted into its bis-chloromethylate.  Specifications 24652/10 and 313,293, [both in Class 2 (iii), Dyes &c.], also are referred to.  Amino- and aminophenoxy-quinolines.  3-Aminoquinaldine is prepared by the action of acetonylphthalimide onisatin. 6-Methylaminoquinoline is produced by treating 6-aminoquinoline with chlorsulphonic acid, methylating the resulting quinoline-6-sulphamic acid with dimethyl sulphate and splitting off the sulphonic acid residue with caustic soda. N-Methyl-1 : 2 : 3 : 4-tetrahydro-6-aminoquinoline results from the reduction of the iodomethylate of 6-nitroquinoline with tin and hydrochloric acid.  6-(p-Aminophenoxy)-quinoline is obtained by treating the potassium salt of 6-hydroxyquinoline with p-nitrochlorobenzene and reducing the product. 5-Chloro-8-aminoisoquinoline is obtained from 5-aminoisoquinoline by converting to 5-chloroisoquinoline by the Sandmeyer process, nitrating and reducing.  Carbonazides.  Quinoline-6-carbonazide is prepared by treating quinoline-6-carboxylic ethylester with hydrazine hydrate and decomposing the resulting carbohydrazide with nitrous acid; m-nitro-p-toluic acid azide and p-dimethylaminobenzoyl azide are similarly obtained from the corresponding acid esters. Bz-Amino-o-phenanthroline is produced by partly reducing 6 : 8-dinitroquinoline to 6-nitro-8-aminoquinoline, converting this by the Skraup synthesis into Bz-nitro-o-phenanthroline and reducing the nitro group.  4-Amino-3<1> : 5<1>-dimethyldiphenylether is obtained by the action of p-nitrochlorobenzene on the sodium compound of sym-xylenol and reducing the resulting nitro compound.